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Sci Signal. 2017 Jun 27;10(485). pii: eaak9916. doi: 10.1126/scisignal.aak9916.

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.

Author information

1
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
2
StemSynergy Therapeutics Inc., Miami, FL 33136, USA.
3
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
4
Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
5
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
6
Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
7
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8
Division of Gastroenterology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
9
Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. drobbins@med.miami.edu.

Abstract

Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.

PMID:
28655862
PMCID:
PMC5555225
DOI:
10.1126/scisignal.aak9916
[Indexed for MEDLINE]
Free PMC Article

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